Drug addiction has been considered a chronic disease and a risk factor for many other diseases and disorders. To better treat addiction and prevent future abuse of illicit drugs, it is essential to understand the mechanisms underlying addictive behaviors. Clinical and animal studies have established that the metabolic status contributes to the determination of reward threshold in humans and animals. Food restriction increases the sensitivity to drugs of abuse, while over-nutrition decreases the sensitivity to drugs. However, it is still elusive how the brain circuitry regulating the metabolic status interacts with the reward circuitry. The lateral hypothalamus (LH), a central hub integrating a wide range of inputs from various brain regions encoding metabolic, behavioral and environmental cues, is a critical brain area to regulate both energy homeostasis and food/drug reward. Specifically, a selective group of neurons exclusively synthesizing the neuropeptide hypocretin (Hcrt, also called orexin) affect food intake and play a prominent role in food award and drug addiction. It is not entirely clear what role the Hcrt system plays in the hierarchy of circuitry responsible for food reward and drug addiction. Recent studies by others and us indicate that the Hcrt system undergoes experience-dependent synaptic plasticity in animals exposed to cocaine, which leads to our overall hypothesis that the expression of experience-dependent synaptic plasticity in Hcrt cells contributes to the development of addictive behaviors in animals. If this is true, the ability to establish synaptic plasticity in Hcrt neurons may contribute to the susceptibility of animals to addictive behaviors. Based on our previous studies, we hypothesize that metabolic/energy status may determine the sensitivity to reward reinforcers through modulating activity and plasticity in Hcrt neurons in animals. In this application stemmed from an R21 grant, we will begin to address this hypothesis by determining whether either over- nutrition or chronic energy deficiency alters the ability of cocaine to trigger plasticity in the Hcrt system with molecular (Hcrt-IRES-Cre mice and DREADDs), cellular (electrophysiological and EM studies) and behavioral (cocaine conditioned place preference) approaches. Three specific aims are: 1) To determine whether over-nutrition causes adaptive changes in Hcrt neurons, which is required in the impairment of drug- seeking behaviors in animals. 2) To test whether chronic energy deficiency leads to adaptation in Hcrt neurons, which facilitates the expression of drug reward in animals. 3) To interrogate whether over-nutrition and energy deficiency-induced adaptations in Hcrt neurons lead to altered responses of target areas of the Hcrt system when animals exposed to cocaine. Our long-term goal is to bridge the knowledge gap in our current understanding of addiction and to bridge the gap between clinical studies and basic research on the role of the Hcrt system in addictive behaviors, an area of study that has not been well explored thus far.